FI61193B - ANALOGIFICATION OF THE PHARMACEUTICAL FORM OF THE PHARMACEUTICAL FORM 2-DEOXY-2-NICOTINAMIDO-1-O-NICOTINOYL-GLUCOPYRANOS-DERIVATIVES - Google Patents

Description

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Switzerland-Switzerland (CH) 1039 / 7U

(71) F. Hofftnann-La Roche & Co. Aktiengesellschaft, Basel, Switzerland-Switzerland (CH) (72) Karl Friedrich Gey, Reinach, Joseph Kiss, Arlesheim, Hans Lengsfeld, Reinach, Pierre-Charles Wyss, Muttenz, Willy Schuep, Birsfelden,

Switzerland-Schweiz (CH) (7U) Oy Kolster Ah (5U) Analogue method for the preparation of pharmaceutically acceptable 2-deoxy-2-nicotine-amido-10-nicotinoyl-glucopyranose derivatives -Analogiförfarande för framställning av farmaceutiskt användhara 2-deoxi nikotinamido-l-0-nikotinoyl-glucopyranos-derivative of

The present invention relates to an analogous process for the preparation of pharmaceutically usable 2-deoxy-2-nicotinamido-1-O-nicotinoyl-glucopyranose derivatives of the general formula CH 2 OR 'RO 2 -f NH-CO-f / y

'"OF

wherein R is alkanoyl or benzoyl having up to 6 carbon atoms.

61193

Examples of alkanoyl residues are acetyl and propionyl.

Preferred compounds of formula I are those wherein R is acetyl.

Examples of compounds of formula I are: 3,4,6-tri-O-acetyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl, D-glucopyranose; 3.4.6-tri-O-propionyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl-N, D-glucopyranose; 3.4.6-Tri-O-benzoyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl-N, D-glucopyranose.

The compounds of the formula I can be prepared in a manner known per se so that, in a compound of the general formula,

CH OR

N “/ ro N- (jh -CO— (f y

\ = - N

wherein X is halogen or an optionally protected hydroxy group and R is as defined above, wherein if X is halogen, this compound may be as the corresponding oxazolinium halide, the residue X is replaced by a nicotinoyloxy residue.

The halogens described by X in the above formula II may be chlorine, bromine, fluorine or iodine, with chlorine and bromine being preferred.

The protected hydroxy groups described by X may be lower alkoxy, aryloxy, acyloxy or a group -O-Z where Z is a heterocyclic residue, e.g. imidazolyl.

The acyloxy radicals described by X may be lower alkanoyloxy, alkoxyalkanoyloxy or aroyloxy radicals having the formula -O-R, wherein R is as defined above.

The acyloxy residues described by X may be lower alkanoyloxy (or aroyloxy) carbonyloxy residues.

Replacement of residue X in a compound of formula II with a nicotinoyloxy residue can be accomplished by reacting this compound with a nicotinic acid derivative.

Thus, for example, a compound of formula II wherein X is halogen or a protected hydroxy group may be reacted with an organic nicotinic acid salt, e.g. a triethylamine or tetrabutylammonium salt.

This reaction may conveniently be carried out in an organic solvent, e.g. acetonitrile, dimethyl sulphoxide, dimethylformamide, nitroalkane, halogenated hydrocarbon or the like at a temperature between about 0 ° C and the reflux temperature of the reaction mixture.

A compound of formula II wherein X is alkanoyloxy. (or aroyloxy) -carbonyloxy, may be reacted with Nicotinic acid or a derivative thereof, e.g. a halide.

This reaction is conveniently carried out in the presence of a solvent, e.g. dimethyl sulfoxide, acetonitrile or the like, at a temperature between 50 ° C and the reflux temperature of the reaction mixture.

A compound of formula II wherein X is a free hydroxy group may be reacted with a nicotinic acid derivative, e.g. nicotinic acid halide, nicotinic acid azide or nicotinic anhydride.

This reaction may conveniently be carried out at a temperature between -10 and 50 ° C and in the presence of a condensing agent such as pyridine or triethylamine.

The compounds of the formula II are known or can be prepared in a manner known per se.

Thus, a compound of formula II wherein X is halogen can be prepared by reacting N-nicotinoyl-D-glucosamine with the corresponding acyl halide of general formula 61193

RX

wherein X is halogen and R is as defined above.

This reaction is conveniently carried out in the presence of an organic solvent, e.g. an ether such as dioxane, a nitroalkane, e.g. nitromethane, a halogenated hydrocarbon, e.g. chloroform, or the like.

In this reaction, temperature is not critical. However, it is expedient to work at a temperature between 50 ° C and 100 ° C.

Compounds of formula II in which X is halogen, namely the compounds of formula II in which Hal is halogen in the following reaction scheme, may be in ionized form, i. in the form of the corresponding oxazolinium halide of formula 11.

CH2OR chzor - <£ >> · ΛΓ \ Λ «= <{Λ

\-OF

ITa IJb

An equilibrium exists between compounds II and II, from which compound IIa or 11 can be isolated, if desired.

A compound of formula II wherein X is a hydroxy residue can be prepared by hydrolysis of the corresponding compound of formula II wherein X is a halogen atom.

The hydrolysis is carried out in the presence of a small amount of water, suitably in the presence of an organic solvent, e.g. ether, nitroalkane, aromatic hydrocarbon or the like, at a temperature between -30μ (2: ββη and room temperature).

5,61193

A compound of formula II / wherein X is an acyloxy residue may be prepared by reacting the corresponding 1,3,4,6-tetra-O-acyl-D-glucosamine with nicotinic acid or a derivative thereof, e.g. an anhydride, halide or activated ester. with, e.g., p-nitrophenyl ester.

The reaction is conveniently carried out in the presence of a condensing agent, e.g. pyridine. In this reaction, the temperature is not critical, however, it is expedient to work at a temperature of 50 to 100 ° C.

A compound of formula II wherein X is a lower alkoxy residue can be obtained by reacting N-nicotinoyl-D-glucosamine catalytically with the corresponding lower alcohol and acylating the 3-, 4- and 6-positions of the 1-alkoxylated compound.

As the catalysts, acids such as hydrochloric acid or sulfuric acid, Lewis acids such as zinc chloride, cation exchange resins or the like can be used. The alkoxylation can be performed at a temperature between 50 ° C and the reflux temperature of the reaction mixture.

The acylation can be performed with the corresponding acyl halide, anhydride or azide. If an acyl halide or azide is used, the reaction is carried out in the presence of a tertiary base, e.g. pyridine, trimethylamine or the like. If anhydride is used, the reaction is carried out in the presence of the corresponding acid of the alkali metal salt in anhydrous form and suitably in the presence of an excess of anhydride. In both cases, the reaction temperature may range from 0 to 100 ° C.

A compound of formula II wherein X is an aryloxy residue may be prepared, e.g., by reacting the corresponding N-nicotinoyl-1,3,4,6-tetra-O-acylglucosamine with the corresponding phenol in the presence of one of the aforementioned acid catalysts.

A compound of formula II wherein X is an alkoxy (or aryloxy) carbonyloxy residue can be prepared by reacting the corresponding compound of formula II wherein X is a hydroxy group with the corresponding haloacid ester.

The compounds of formula I have a plasma lipid lowering effect. A preferred property of these compounds is the slow degradation of nicotinic acid from these compounds, resulting in a long lasting increase in plasma nicotinic acid concentration. This results in a long-lasting decrease in plasma lipids. Thus, once administered 3,4,6-tri-O-acetyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl-β-D-glucopyranose or 3,4,6-tri-O-propionyl- 2-deoxy-2-nicotinamido-1-O-nicotinoyl-γ6-D-glucopyranose rats decreased plasma triglyceride levels above 13 for 7-13 hours, respectively. The toxicity (LD ^ q) of the former substance in rats is greater than 6000 mg / kg on a given tenth day after five oral administrations.

In contrast to the compounds of the formula I, the plasma lipid-reducing β-pyridylcarbinol, nicotinic acid and nicotine esters, such as nikeritrol, nicofuranose or Swiss patent 341 806, U.S. Pat. No. 3,133,912 and Norwegian Patent Publication No. do not contain any 2-deoxy-2-nicotinamido-1-O-nicotinoyl-glucopyranose moiety.

Compared to known compounds containing one or more pyridyl residues, which, when administered to rats at 1 mmol / kg (based on pyridyl residues), produce a sudden and short-lasting maximum plasma nicotine concentration, the compounds of formula I provide a more uniform and long-lasting increase in nicotinic acid concentration over time. Similarly, when the compounds of the formula I are administered, the reduction in free fatty acids, cholesterol and triglycerides in the plasma is maintained for several hours longer than when the above-mentioned known compounds are administered. For example, it has been shown that when administered 3,4,6-tri-O-acetyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl-4-D-glucopyranose (a compound of formula I wherein R is acetyl) the triglycerides are reduced for at least 6 hours longer than when β-pyridylcarbinol was administered.

The compounds of formula I are conveniently administered in an amount of about 10 to 100 mg / kg per day.

However, the dosages set forth above are exemplary only and may be varied up or down in accordance with the present conditions or modes of administration.

61193

Pharmaceutical preparations for lowering lipid levels in plasma can be prepared by adding a compound of formula I as active ingredient to non-toxic, inert, solid or liquid carriers suitable for therapeutic administration as such in such preparations.

Examples of such carriers are water, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, etc. The pharmaceutical preparations may be in solid form, e.g. tablets, granules, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. Optionally, they may be sterilized or contain adjuvants such as preservatives, stabilizers, wetting or foaming agents, salts for varying the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

The preferred form of administration is tablets containing about 100 to 1000 mg of active ingredient.

Example 1 2 g of 2-deoxy-2-nicotinamido-1-3,6,6-tetra-O-acetyl-0, D-glucopyranose are dissolved in 150 ml of methylene chloride and 2 ml of acetyl chloride are added. Hydrogen chloride is introduced into this solution with stirring for 1 hour. The solution is allowed to stand in the refrigerator for 48 hours, then 100 ml of ice water are added and the mixture is neutralized with 2N sodium carbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. The residue is dissolved in 30 ml of acetonitrile, a solution of the nicotinic acid triethylamine salt (obtained from 0.65 g of nicotinic acid and 20 ml of triethylamine) in 20 ml of acetonitrile is added and stirred overnight.

The mixture is evaporated, dissolved in 100 ml of chloroform and washed three times with 50 ml of water. The organic phase is separated, dried over sodium sulfate, evaporated and crystallized from ethanol. 0.550 g (24.2%) of 3,4,6-tri-O-acetyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl-β, D-glucopyranose are obtained. Sp. 172-173 ° C.

The tetraacetylglucopyranose used as starting material can be prepared as follows: β 61193 24 g of 2-amino-2-deoxy-1,3,4,6-tetra-O-acetyl-, 1,2-glucopyranose hydrochloride are dissolved in 150 ml of pyridine and is added to a mixture of 20 g of nicotinic acid hydrochloride in 150 ml of pyridine. The mixture is stirred for 2 hours and then evaporated to dryness. The residue is dissolved in 500 ml of chloroform and washed with saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated again. After crystallization from ethanol, 29.5 g of substance are obtained. Sp. 218-219 ° C.

Example 2 A solution of 3,4,6-tri-O-acetyl-2-deoxy-2-nicotinamido-1-chloro-N-nicotinoyl-D-glucosamine and 300 ml of acetyl chloride from 100 g of acetyl chloride , D-glucopyranose, dilute with 1.2 liters of methylene chloride and pour into 1.2 liters of ice water. The pH of the mixture is adjusted to 5-6 with 2N sodium carbonate solution with stirring. The organic phase is separated, dried over magnesium sulphate and evaporated to dryness. The residue is dissolved in 500 ml of acetonitrile, a solution of the salt obtained from 70 g of nicotinic acid and 150 ml of triethylamine is added and stirred overnight. The solution is evaporated, dissolved in 1 liter of chloroform, washed three times with 1.5 liters of water, dried over sodium sulfate and evaporated again. The residue is dissolved in 1.5 liters of ethanol, treated with 20 g of activated carbon, filtered off with suction and evaporated to 1/3 of the original volume. After crystallization from an alcoholic solution and recrystallization twice from ethanol, 48 g (26.5%) of 3,4,6-tri-O-acetyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl- 5, D-glucopyranose. Sp. 175-176 ° C.

Example 3

A suspension of 10 g of N-nicotinoyl-D-glucose amine in 30 ml of propionic acid chloride is stirred for 18 hours at room temperature and the resulting solution is evaporated to dryness. The residue is dissolved in 150 ml of methylene chloride and poured into 150 ml of ice water. After adjusting the pH of the reaction mixture to 7 with 2N sodium carbonate solution, the organic phase is dried over magnesium sulphate and the solution is evaporated to dryness. To a solution of the residue in 50 ml of acetonitrile is added triethylammonium nicotinate (obtained from 6.5 g of nicotinic acid and 15 ml of triethylamine) and stirred overnight at room temperature. After evaporation of the reaction mixture, the residue is dissolved in 250 ml of methylene chloride and the organic phase is washed twice with 100 ml of water, dried over magnesium sulphate and evaporated. After crystallization from ethyl acetate-isopropyl ether and recrystallization from isopropanol, 3.3 g (16.8%) of 3,4,6-tri-O-propionyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl- / 5, D-glucopyranose. Sp. 161 ° C.

Example 4

The methylene chloride is saturated with hydrogen chloride and 0.5 g of 1,3,4,6-tetra-O-benzoyl-2-deoxy-2-nicotinamido-N, D-glucopyranose (m.p. 195-196 °) is dissolved in 5 ml of the resulting solution. C). The solution is allowed to stand for 24 hours at room temperature.

The solution is then evaporated to dryness and the residue is dissolved in 20 ml of methylene chloride and poured into 10 ml of ice water.

After the pH of the reaction mixture is reached 7 with 2N sodium carbonate solution, the organic phase is dried over magnesium sulphate and the solution is evaporated to dryness. To a solution of the residue in 10 ml of acetonitrile is added triethylammonium nicotinate (obtained from 0.15 g of nicotinic acid and 3 ml of triethylamine) and stirred overnight at room temperature. After evaporation of the reaction mixture, the residue is dissolved in 25 ml of methylene chloride and the organic phase is washed twice with 10 ml of water, dried over magnesium sulphate and evaporated. The mixture is applied to a silica gel column (150 g) and eluted with chloroform-ethanol (19: 1). After crystallization and recrystallization from pure ethanol, 0.1 g (20%) of 3,4,6-tri-O-benzoyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl 11- / 5 / D is obtained. -glukopyranoosia. Sp. 178 ° C.

Claims (2)

61193 10 An analogous process for the preparation of pharmaceutically usable 2-deoxy-2-nicotinamido-1-O-nicotinoyl-glucopyranose derivatives of the general formula CH that in a compound of the formula CH 2 OR NH-CO-Y wherein X is halogen or an optionally protected hydroxy group and R is as defined above, wherein if X is halogen, the compound may be in the form of the corresponding oxazolinium halide, the residue X is replaced by a nicotinoyloxy residue . Process for the preparation of 3,4,6-tri-O-acetyl-2-deoxy-2-nicotinamido-1-O-nicotinoyl-β, D-Glu-copyranose according to Claim 1, characterized in that the starting material used is the formula II wherein R is acetyl.